Method for Preparing a Granulate Formulation of Pirfenidone and Pharmaceutically Acceptable Excipients

ABSTRACT

A capsule formulation of pirfenidone is provided that includes pharmaceutically acceptable excipients. In one embodiment, this capsule formulation is capable of sustaining desirable pharmacokinetic responses in a patient. Further provided are methods of treating fibrotic conditions and other cytokine-mediated disorders by administering pirfenidone capsules of such formulation to a patient in need.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 13/776,079filed Feb. 25, 2013, which is a continuation of U.S. patent applicationSer. No. 13/162,048 filed Jun. 16, 2011, which is a continuation of U.S.patent application Ser. No. 12/067,712, filed Jul. 14, 2008 (U.S. Pat.No. 7,988,994) which is the U.S. National Phase Under 35 U.S.C. §371 ofPCT/US2006/037057 filed Sep. 22, 2006, which in turn claims priority toU.S. Ser. No. 60/720,257 filed Sep. 22, 2005, the disclosures of whichare hereby incorporated herein by reference.

BACKGROUND OF THE DISCLOSURE

1. Field of the Disclosure

The present disclosure relates in general to pirfenidone, a small drugmolecule whose chemical name is 5-methyl-1-phenyl-2-(1H)-pyridone.Specifically, the present disclosure relates to a capsule formulation ofpirfenidone including pharmaceutically acceptable excipients. Furtherprovided are methods of using such capsule formulation in the treatmentof fibrotic conditions and other disorders mediated by cytokines.

2. Description of the Related Art

Pirfenidone is a non-peptide synthetic molecule with a molecular weightof 185.23 daltons. Its chemical elements are expressed as C₁₂H₁₁NO, andits structure is known. The synthesis of pirfenidone has been workedout. Pirfenidone is manufactured and being evaluated clinically as abroad-spectrum anti-fibrotic drug. Pirfenidone has anti-fibroticproperties via: decreased TNF-α expression, decreased PDGF expression,and decreased collagen expression. Several pirfenidone InvestigationalNew Drug Applications (INDs) are currently on file with the U.S. Foodand Drug Administration. Phase II human investigations are ongoing orhave recently been completed for pulmonary fibrosis, renalglomerulosclerosis, and liver cirrhosis. There have been other Phase IIstudies that used pirfenidone to treat benign prostate hypertrophy,hypertrophic scarring (keloids), and rheumatoid arthritis.

One important use of pirfenidone is known to be providing therapeuticbenefits to patients suffering from fibrosis conditions such asHermansky-Pudlak Syndrome (HPS) associated pulmonary fibrosis andidiopathic pulmonary fibrosis (IPF). Pirfenidone demonstrates apharmacologic ability to prevent or remove excessive scar tissue foundin fibrosis associated with injured tissues including that of lungs,skin, joints, kidneys, prostate glands, and livers. Published andunpublished basic and clinical research suggests that pirfenidone maysafely slow or inhibit the progressive enlargement of fibrotic lesions,remove pre-existing fibrotic lesions, and prevent formation of newfibrotic lesions following tissue injuries.

It is understood that one mechanism by which pirfenidone exerts itstherapeutic effects is modulating cytokine actions. Pirfenidone is apotent inhibitor of fibrogenic cytokines and TNF-α. It is welldocumented that pirfenidone inhibits excessive biosynthesis or releaseof various fibrogenic cytokines such as TGF-β1, bFGF, PDGF, and EGF.Zhang S et al., Australian and New England Journal Ophthalmology, 26;S74-S76, 1998. Experimental reports also show that pirfenidone blocksthe synthesis and release of excessive amounts of TNF-α from macrophagesand other cells. Cain et al., International Journal Immunopharmacology,20:685-695 (1998).

As an investigational drug, pirfenidone is provided in tablet andcapsule forms principally for oral administration. Various formulationshave been tested and adopted in clinical trials and other research andexperiments. The effectiveness of a formulation may be determined by aplurality of factors, including the amount of pirfenidone it contains,the kinds and relative amounts of pharmacologically acceptableexcipients used, and the target patient profile (e.g., the physiologicaland genetic conditions, disease prognosis, and demographiccharacteristics of the patient). Changes in these factors cause changesin pharmacokinetic (PK) responses in the patient. Thus, there is a needin general for effective pharmaceutical formulations that elicitdesirable pharmacokinetic responses in patients thereby optimizingtherapeutic actions of pirfenidone.

SUMMARY OF THE VARIOUS EMBODIMENTS

It is therefore an object of this disclosure to provide pharmaceuticalformulations of pirfenidone capable of advantageous therapeutic actions.It is a related object to provide pharmaceutical formulations ofpirfenidone capable of eliciting and sustaining desirablepharmacokinetic responses in the patient in need thereof. It is anotherobject of this disclosure to provide methods for treating fibroticconditions and other cytokine-mediated disorders using suchformulations.

In accordance with this disclosure, there is provided, in oneembodiment, a capsule having a pharmaceutical formulation of5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone), which includes 5-30% ofpharmaceutically acceptable excipients and 70-95% of pirfenidone byweight.

According to another embodiment, the excipients include disintegrators,binders, fillers, and lubricants. Examples of disintegrators includeagar-agar, algins, calcium carbonate, carboxmethylcellulose, cellulose,clays, colloid silicon dioxide, croscarmellose sodium, crospovidone,gums, magnesium aluminium silicate, methylcellulose, polacrilinpotassium, sodium alginate, low substituted hydroxypropylcellulose, andcross-linked polyvinylpyrrolidone hydroxypropylcellulose, sodium starchglycolate, and starch. Examples of binders include microcrystallinecellulose, hydroxymethyl cellulose, hydroxypropylcellulose, andpolyvinylpyrrolidone. Examples of fillers include calcium carbonate,calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate,calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin,dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesiumoxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose,sugar, and xylitol. Examples of lubricants include agar, calciumstearate, ethyl oleate, ethyl laureate, glycerin, glycerylpalmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesiumstearate, mannitol, poloxamer, glycols, sodium benzoate, sodium laurylsulfate, sodium stearyl, sorbitol, stearic acid, talc, and zincstearate.

According to yet another embodiment, by weight 2-10% of the capsule isdisintegrator, 2-30% is binder, 2-30% is filler, and 0.3-0.8% islubricant. In another embodiment, by weight 2-10% of the capsule isdisintegrator, 2-25% is binder, 2-25% is filler, and 0.3-0.8% islubricant. According to still another embodiment, the excipients furtherinclude povidone. In a further embodiment, by weight 1-4% of the capsuleis povidone. According to another embodiment, the capsule includes100-400 mg Pirfenidone.

In accordance with this disclosure, there is provided, in anotherembodiment, a method for treating a fibrotic condition. The methodcomprises administering the aforementioned capsule to a patientsuffering from the fibrotic condition. Examples of such fibroticconditions include pulmonary fibrosis, hepatic fibrosis, cardiacfibrosis, keloid, dermal fibrosis, coronary restenosis, andpost-surgical adhesions. Examples of pulmonary fibrosis includeidiopathic pulmonary fibrosis and Hermansky-Pudlak Syndromes.

In accordance with this disclosure, there is provided, in yet anotherembodiment, a method for inhibiting actions of cytokines in a patientsuffering from a disorder mediated by such cytokines. The methodcomprises administering the aforementioned capsule to the patient.Examples of such cytokines include TNF-α, TGF-β1, bFGF, PDGF, and EGF.Examples of such disorder include multiple sclerosis, arthritis, asthma,chronic rhinitis, and edema. In still another embodiment, the methodfurther comprises administering one or more capsules to the patient oneor more times a day, with a total daily intake of pirfenidone greaterthan 1200 mg. In various embodiments, the patient is given one or morecapsules twice or three times a day.

In accordance with this disclosure, there is provided, in still anotherembodiment, a capsule having an effective amount of pirfenidone andpharmaceutically acceptable excipients. The capsule when administered ina patient is capable of sustaining a measurable pharmacokineticresponse. The pharmacokinetic response is characterized by an increasein the T_(max) or AUC values than a pirfenidone capsule containing nopharmaceutically acceptable excipients. In various embodiments,treatment methods of administering such capsules are provided forpatients suffering from fibrotic conditions such as idiopathic pulmonaryfibrosis and Hermansky-Pudlak Syndrome, and other disorders mediated bycytokines such as TNF-a, TGF-β1, bFGF, PDGF, and EGF.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows changes in the mean serum concentrations of pirfenidone andits metabolite 5-carboxylic acid over time in human subjects included inone of the previously reported pharmacokinetic studies: Shionogi PhaseII.

FIG. 2 is a table that shows quantitative compositions of thepirfenidone tablets used in Shionogi Phase II.

FIG. 3 shows changes in pirfenidone serum concentrations over time inhuman subjects after a single dose of 400 mg pirfenidone deliveredorally in capsules without excipients.

FIG. 4 shows changes in pirfenidone serum concentrations over time inhuman objects following a single dose of 200-300 mg pirfenidonedelivered orally in capsules with excipients, according to oneembodiment of this disclosure.

FIG. 5 is a table that shows the PK values of the capsules withexcipients according to one embodiment of this disclosure, compared tothe PK values of capsules without excipients of one of the previouslyreported PK studies.

FIG. 6 is a table that shows the formulation ofpirfenidone/excipient-containing capsules used in the study depicted inFIG. 4 and the study depicted in FIG. 8 a-c.

FIG. 7 is a table that lists the components used to prepare arepresentative batch of the pirfenidone/excipient formulation of FIG. 6.

FIGS. 8 a-c lists tables that show the stability of thepirfenidone/excipient formulation of FIG. 6 at 25° C. and 60% relativehumidity (FIG. 8 a), 35° C. and 65% relative humidity (FIG. 8 b), and40° C. and 75% relative humidity (FIG. 8 c).

FIGS. 9 a and 9 b depict additional representative formulation ofpirfenidone/excipient-containing capsules contemplated herein.

DETAILED DESCRIPTION OF THE VARIOUS EMBODIMENTS Discussion of theRelevant Terms

Throughout the present disclosure relevant terms are to be understoodconsistently with their typical meanings established in the relevantart, i.e. the art of pharmaceutical chemistry, medicine, biology,genetics, molecular biology, biochemistry, physiology, genomics,pharmacogenomics, bioinformatics, computational biology, andcheminfomatics. However, further clarifications and descriptions areprovided for certain terms as set forth below:

The terms pharmaceuticals, pharmaceutical products, drug products, drugchemicals, drug compounds, compounds, and chemicals, are usedinterchangeably throughout this disclosure.

API, as used herein, refers to active pharmaceutical ingredients. Invarious embodiments of this disclosure, the API of the capsule andtablet formulations is pirfenidone.

The terms pharmaceutically acceptable excipients, pharmaceuticallycompatible excipients, and excipients are used interchangeably in thisdisclosure. They refer to non-API substances such as disintegrators,binders, fillers, and lubricants used in formulating pharmaceuticalproducts. They are generally safe for administering to humans accordingto established governmental standards, including those promulgated bythe United States Food and Drug Administration.

Disintegrators, as used herein, refer to one or more of agar-agar,algins, calcium carbonate, carboxmethylcellulose, cellulose, clays,colloid silicon dioxide, croscarmellose sodium, crospovidone, gums,magnesium aluminium silicate, methylcellulose, polacrilin potassium,sodium alginate, low substituted hydroxypropylcellulose, andcross-linked polyvinylpyrrolidone hydroxypropylcellulose, sodium starchglycolate, and starch.

Binders, as used herein, refer to one or more of microcrystallinecellulose, hydroxymethyl cellulose, hydroxypropylcellulose, andpolyvinylpyrrolidone.

Fillers, as used herein, refer to one or more of calcium carbonate,calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate,calcium carboxymethylcellulose, cellulose, dextrin derivatives, dextrin,dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesiumoxide, maltitol, maltodextrins, maltose, sorbitol, starch, sucrose,sugar, and xylitol.

Lubricants, as used herein, refer to one or more of agar, calciumstearate, ethyl oleate, ethyl laureate, glycerin, glycerylpalmitostearate, hydrogenated vegetable oil, magnesium oxide, magnesiumstearate, mannitol, poloxamer, glycols, sodium benzoate, sodium laurylsulfate, sodium stearyl, sorbitol, stearic acid, talc, and zincstearate.

Capsule, as used herein, refers to a generally safe, readily dissolvableenclosure for carrying certain pharmaceutical products. In oneembodiment, capsule is made of gelatin. Other suitable matrix substancessuch as total synthetic polymer chemicals having gelatin-like propertiesmay be used to manufacture pirfenidone capsules according to alternativeembodiments of this disclosure.

AUC, as used herein, refers to the area under the curve that representschanges in blood concentrations of pirfenidone over time.

C_(max), as used herein, refers to the maximum value of bloodconcentration shown on the curve that represents changes in bloodconcentrations of pirfenidone over time.

T_(max), as used herein, refers to the time that it takes forpirfenidone blood concentration to reach the maximum value.

T_(1/2), as used in this disclosure, refers to the time that it takesfor pirfenidone blood concentration to decline to one-half of themaximum level.

Collectively AUC, C_(max), T_(max), and T_(1/2) are the principlepharmacokinetic parameters that characterize the pharmacokineticresponses of a particular drug product such as pirfenidone in an animalor human subject.

Reported Pharmacokinetic Studies on Pirfenidone

Several pharmacokinetic studies on human subjects have been reported,including one in healthy adult males (Schmidt R M, Ritter A and MargolinS, 1974 Bioavailability of Pirfenidone Capsules Following OralAdministration (Human Volunteers) (60-244-73), Oct. 11, 1974. AffiliatedMedical Research, Inc., Princeton, N.J., hereafter “Schmidt 1974”), andtwo in patients with pulmonary fibrosis (Nagai S, Hamada K, ShigematsuM, Taniyama M, Yamauchi S and Izumi T, 2002, Open Label CompassionateUse One Year-Treatment with Pirfenidone to Patients with ChronicPulmonary Fibrosis, Intern Med 41: 1118-1123, hereafter “Nagai 2002”;and Azuma A, Nukiwa T, Tsuboi E et al, 2005, Double-Blind, PlaceboControlled Trial of Pirfenidone in Patients with Idiopathic PulmonaryFibrosis, Am J Respir Crit. Care Med., hereafter “Shionogi Phase II”).

One additional pharmacokinetic study was conducted on a single dose offour 100 mg capsules each containing 100% pirfenidone. Pirfenidone wasadministered orally to 10 healthy adult males at doses of 100, 200, and400 mg. On day 1, a single dose of 100 mg was given to each subject. Onday 3, a single dose of 200 mg was given to each subject. And on day 4,a last single dose of 400 mg was given to each subject. This last singledose of 400 mg was analyzed for pharmacokinetics. Blood plasma sampleswere collected before dosing and at 0.25, 1, 4, and 6 hr after dosing.Pirfenidone concentrations in plasma were determined by gaschromatography. The resulting values of pharmacokinetic parameters are:C_(max)=6.3+2.5 μg/mL, T_(max)=0.9±0.3 hrs, AUC_(6hr)=20.8±10.0μg/mL-hr, and T_(1/2)=2.2±0.6 hrs.

Nagai 2002 involved 10 male patients with pulmonary fibrosis. Thesubjects underwent dose escalation starting with an initial dose of 400mg for several days to a maintenance dose of 40 mg/kg/day.Pharmacokinetics analyses were done on each of the 10 subjects on day 1when a dose of 400 mg was given. Plasma samples were collected at 0,0.25, 1, 1.5, 2, 4, 6, 8, and 24 hr after dosing. The values ofpharmacokinetic parameters were computed. C_(max) was 3.0 to 7.2 μg/mL,and AUC₂₄ hr was 16.9 to 66.4 μg/mL·hr.

Shionogi Phase II involved serial sampling in a 15-patient subset of apirfenidone cohort (13 males and 2 females). On day 1 a 200 mg singledose was given to each of the 15 patients, and serum samples werecollected before dosing and at 0.5, 1, 2, and 3 hr after dosing. Bloodconcentrations of pirfenidone were determined by HPLC assay. FIG. 1demonstrates changes in the observed mean serum concentrations ofpirfenidone and its metabolite 5-carboxylic acid over time. The valuesof pharmacokinetic parameters were computed to be: C_(max)=2.7±0.7μg/mL, T_(max)=1.8±1.1 hrs, AUC_(4hr)=7.3±1.6 μg/mL·hr, andT_(1/2)=3.5±2.2 hrs.

The drug formulations in these previously reported studies weredifferent. Schmidt 1974 used a capsule including 100% pirfenidone. Nagai2002 and Shionogi Phase II used pirfenidone tablets that includedcertain pharmaceutically acceptable excipients. For example, the drugproduct used in Shionogi Phase II was formulated as compressed, coatedtablets of 200 mg of pirfenidone. Shionogi Phase II tablets includedpharmaceutically acceptable excipients. FIG. 2 is a table listing theingredients of the Shionogi Phase II tablets and the quantities of eachingredient. As shown, the core tablet was 285 mg, of which 200 mg wasAPI. Various amounts of disintegrator, filler, binder, and lubricantwere included. With the addition of the coating, the total weight of theShionogi Phase II tablet was 296.4 mg.

Schmidt 1974 examined the pharmacokinetics of single dose pirfenidone.Ten human volunteers were included in this study. At 15 minutes afteroral ingestion of 400 mg pirfenidone, the average serum concentration ofpirfenidone reached 3.97 mg/mL. At one hour, the average serumconcentration was measured to be 5.57 mg/mL, and at six hour 1.63 mg/mL.FIG. 3 is a plot of serum pirfenidone levels over time summarizing thisstudy. As shown, the maximum serum pirfenidone level was reached betweenone and three hours. The value of T_(1/2) was calculated to be 2.87+0.22hrs.

Capsule Formulation of Pirfenidone with Excipients

To those skilled in the pharmaceutical research and manufacturing, it isgenerally known that tablet formulations permit generous additions ofnon-API ingredients including excipients and coating substances,especially high percentage of fillers. However, the addition of non-APIingredients may limit the amount of API carried in each tablet. Bycontrast, capsule formulations tend to facilitate the inclusion of highpercentage of API with no or less non-API components. Capsules may allowfor inclusion of a larger amount of binders, instead of fillers as usedmore in tablets. Where high percentage of API is desired and specificexcipients are not known to be essential, capsule formulations are oftenadopted.

To be sure, no capsule formulation of pirfenidone manufactured orreported to date contains excipients. The present disclosure provides anew pirfenidone capsule formulation with certain pharmaceuticallyacceptable excipients. According to one embodiment, this new capsuleformulation is capable of eliciting advantageous pharmacokineticresponses in human subjects. In another embodiment, this new capsuleformulation facilitates dissolution and improves flowability in thecapsule manufacturing process.

This capsule formulation includes 100-400 mg pirfenidone. One or morepharmaceutically acceptable excipients are added in various embodiments.For example, in one embodiment, by weight 2-10% of the capsule isdisintegrator, 2-30% is binder, 2-30% is filler, and 0.3-0.8% islubricant. As described in the beginning of this Detailed Description, amultitude of substances may be suitably included as disintegrator,binder, filler, and lubricant. One example is to use magnesium stearateas lubricant, microcrystalline cellulose as binder, and croscarmelloseas disintegrator. In a particular embodiment, the capsule formulationfurther includes povidone. By weight povidone may constitute 1-4% of thecapsule.

The capsule shell may be made of hard gelatin in one embodiment. Theshell may be clear or opaque, white or with color in variousembodiments. The capsule is size 1 in a preferred embodiment. Othersizes may be adopted in alternative embodiments.

The manufacture of pirfenidone capsules based on the capsule formulationof the various embodiments includes a series of steps. These steps are:preparing pirfenidone granulation, fluid bed drying, milling,lubrication blend, encapsulation, and bulk packaging

The preparation of pirfenidone granulation may be done in the followingsequence. First, povidone is mixed with water and dissolved using anoverhead mixer. Second, pirfenidone is milled with croscarmellose andmicrocrystalline cellulose to break up any lumps. Third, the milledpirfenidone, croscarmellose, and microcrystalline cellulose are addedinto a high sheer granulator and blended. Fourth, the povidone and watersolution is added to the blend. Fifth, the pirfenidone granulation isblended for an additional period of time after the povidone and watersolution have been completely added.

The fluid bed drying process may be performed on a Fluid Bed Dryer withan inlet temperature of 60° C. The milling process may be performedusing a suitable miller such as Quadro Comil®. The lubrication blendprocess may be conducted with the addition of an appropriate amount ofcroscarmellose and magnesium stearate. The pirfenidone granulation maybe further blended at this point. Next the pirfenidone granulation isencapsulated using a suitable encapsulator into two-piece, size 1,gelatin capsules to yield a desired pirfenidone dose of 100-400 mg. Thedose of 200-300 mg is yielded in a preferred embodiment. To conclude thecapsule manufacturing process, finished capsules may be packaged insecured, double polybags and stored at controlled room temperature.Those skilled in drug research and drug making will appreciate thatcertain of the aforementioned steps may be modified or omitted, andadditional steps may be included, without materially altering theoutcome of the manufacturing.

An exemplary composition of the pirfenidone/excipientformulation-containing capsules that was prepared and tested is providedin FIG. 6. A representative batch of the pirfenidone/excipientformulation was prepared using routine wet formulation methods tocombine the components listed in FIG. 7.

Pharmacokinetic studies were performed on the pirfenidone capsules ofthe present disclosure. A first study depicted in FIG. 4 shows averagechanges in serum concentrations over time in four groups of subjects towhom were administered a single dose of the 267 mg pirfenidone capsuleformulation of FIG. 6. The four lines of this graph, A, B, C, and D,represent four different groups of subjects: A, fasted subjects; B,fasted subjected with antacid administered; C, fed subjects; and D, edsubjects with antacid administered.

In another pharmacokinetic study, two groups of human subjects on normaldiet were included, each having 13 subjects. One group (Group I)received no antacid, while the other group (Group II) received antacid.The 267 mg pirfenidone capsule formulation of FIG. 6 was given to eachsubject. FIG. 5 is a table summarizing the resulting PK values for bothgroups (Capsule Groups I and II), compared to the PK values reported inthe one additional pharmacokinetic study of a capsule of pirfenidoneonly. As demonstrated in FIG. 5, T_(max) is significantly longer (anapproximately two-fold increase in each of Groups I and II) for theseexcipient-containing capsules than what was reported in the oneadditional pharmacokinetic study of a capsule of pirfenidone only. AUCis also significantly higher for these excipient-containing capsulesthan what was reported in the one additional pharmacokinetic study of acapsule of pirfenidone only. AUC values are computed over a time periodof zero to infinity. The values of C_(max) and T_(1/2) are also higherthan or comparable with those reported in the one additionalpharmacokinetic study of a capsule of pirfenidone only.

These resulting PK values, especially the increased T_(max) and AUC,indicate a prolonged absorption phase for the pirfenidone capsules withexcipients according to the present disclosure. Consequently, thesecapsules are capable of sustaining prolonged therapeutic actions in apatient. Therefore, compared to the capsules without excipients, as whatwere used in Schmidt 1974, the capsule formulation with the excipientsmay be advantageously administered to a patient in need, therebyeliciting desirable pharmacokinetic responses in the patient. Whilstsuch desirable PK responses are surprising results, it is conceivablethat binders such as microcrystalline cellulose or povidone favorablyinteract with the amide carbonyl group of pirfenidone forming atransient complex which may then dissociate, resulting in a slowbuild-up in the plasma concentration of pirfenidone, or a slow declineor clearance in the plasma concentration.

In addition to the therapeutic advantages of the pirfenidone/excipientformulations provided herein, these capsules and the formulations alsoshow good stability under various storage conditions over time. In someembodiments, under various storage conditions the capsules andpirfenidone/excipient formulations provided herein can be stable for atleast, or at least about, 3 months, 6 months, 9 months, 12 months, 15months, 18 months, 24 months, 36 months, or 48 months. For example,under storage conditions of 25° C. and 60% relative humidity, thecapsules and pirfenidone/excipient formulations provided herein can bestable for at least, or at least about, 3 months, 6 months, 9 months, 12months, 15 months, 18 months, 24 months, 36 months, or 48 months. Inanother example, under storage conditions of 30° C. and 65% relativehumidity, the capsules and pirfenidone/excipient formulations providedherein can be stable for at least, or at least about, 3 months, 6months, 9 months, 12 months, 15 months, 18 months, 24 months, 36 months,or 48 months. In another example, under storage conditions of 40° C. and75% relative humidity, the capsules and pirfenidone/excipientformulations provided herein can be stable for at least, or at leastabout, 3 months, 6 months, 9 months, or 12 months.

In some embodiments, the stability of the capsules andpirfenidone/excipient formulations provided herein is determined bymeasuring the dissolution rate of the stored capsule and/orpirfenidone/excipient formulations. Any of a variety of dissolutionmethods provided herein or otherwise known in the art can be performedto determine the stability of capsules and pirfenidone/excipientformulations. Dissolution measurements are in vitro methods known in theart to be representative of in vivo T_(max) and AUC values. Accordingly,the stability of the capsules and pirfenidone/excipient formulations asmeasured by dissolution methods will be representative of the in vivoT_(max) and AUC values of a subject when the capsules andpirfenidone/excipient formulations after storage, for example, under theabove-exemplified conditions for the indicated amount of time.Typically, a dissolution level indicative of an acceptable level ofstability is a dissolution of at least, or at least about 80%, 85%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, of the pirfenidonein the capsules provided herein. Any of a variety of dissolution methodsprovided herein or otherwise known in the art can be performed todetermine the stability of capsules and pirfenidone/excipientformulations. For example, dissolution can be determined according tothe pharmacopoeial dissolution method specified in USP29.

The stability of the capsules and pirfenidone/excipient formulationsprovided herein is demonstrated in the results presented in FIG. 8. The267 mg pirfenidone capsule formulation of FIG. 6 was stored for 18months under three different storage conditions: 25° C. and 60% relativehumidity, 30° C. and 65% relative humidity, and 40° C. and 75% relativehumidity. FIG. 8 shows that the dissolution of the capsule andpirfenidone/excipient formulations at 25° C. and 60% relative humidity,30° C. and 65% relative humidity did not appreciably change over theduration of the 18 month period. The dissolution of the capsule andpirfenidone/excipient formulations at 40° C. and 75% relative humiditydid not appreciably change over the initial 12 month period. Thedissolution analysis was performed according to the pharmacopoeialdissolution method specified in USP29 using Apparatus 2 (paddles) withwater as a solvent and a specification of Q≧70% of label claim in 30minutes. Also shown in FIG. 8, the level of impurities in eachformulation, as determined by HPLC, was less than 0.05% over theduration of the 18 month period. In addition, the moisture content, asdetermined by the Karl Fischer method, of all but one time point (40°C., 75% RH at 18 months) remained below 2%, and the moisture content ofall samples remained below 2.5% over the duration of the 18 monthperiod. Finally, the percent of pirfenidone in each sample, asdetermined by HPLC, showed no appreciable degradation over the 18 monthperiod.

In addition to the specific formulation provided herein in FIG. 6,further formulations contemplated herein are provided in FIGS. 9 a and 9b.

Therapeutic Indications

One embodiment of this disclosure provides methods for treating fibroticconditions and other cytokine-mediated disorders. These methods compriseadministering the excipients-containing pirfenidone capsules of thisdisclosure to a patient suffering from a fibrotic condition or acytokine-mediated disorder. The dosing may be twice or three timesdaily, with one or more capsules per intake. According to a particularlyembodiment, the total daily intake is at least 1200 mg pirfenidone. Thetotal daily intake amount may vary, depending on the patient profile,including among other things the patient's demographic characteristics,physiological and genetic conditions, and disease prognosis. Forexample, a child or a senior person may be given a lower amount dailythan that given to an ordinary adult.

The anti-fibrotic activity of pirfenidone is demonstrated in in vivoanimal fibrosis models, as well as in vitro cell culture studies withhuman or animal lung fibroblasts, dermal fibroblasts, andfibroblast-like cells. Those data indicates that pirfenidone may be aneffective agent for preventing and treating post-surgical adhesions,myocardial fibrosis, renal fibrosis, liver cirrhosis, atherosclerosis,and other fibrotic disorders. In vitro cell cultures with humanmesenchymal-like cells (including lung fibroblasts, skin fibroblasts,prostate stromal cells, and renal mesangial cells, etc) have shownpharmacologic inhibition by pirfenidone of excessive cell proliferationinduced by cytokine growth factors (TGF-β1, bFGF, PDGF, and EGF). Incell culture media, graded concentrations of pirfenidone were effectiveat levels which were ten to twenty times lower than those exerting anypharmacologically toxic effects on the cells.

At the site of injury, otherwise normal resident cells (e.g.,fibroblasts, pericytes, mesangial cells, astrocytes, microglia, andoligodendrocytes) manufacture and discharge high concentrations ofgrowth factors into adjacent tissue spaces. These resident sources ofpathologically high levels of growth factors are directly responsiblefor the persistently excessive levels of growth factors. They causeexcessive and harmful formation of collagen or amyloid matrix as well asdamage to adjacent cells, the associated organ dysfunction, andfrequently, organ malformation.

TGF-β1 is a potent growth-related peptide whose effects may be observedat femtomolar concentrations. It appears to be ubiquitous, and is abifunctional regulator of cell proliferation in vitro. It acts either asa mitogen or a growth inhibitor depending on tissue concentration andthe state of cell confluence (L. J. Striker et al., Lab. Invest.64:446-456, 1991). In skin incisions, after attracting macrophages andfibroblasts, TGF-β1 enhances extracellular matrix formation byincreasing transcription of genes for collagen and fibronectin,decreasing secretion of proteases, increasing secretion of proteaseinhibitors, and increasing transcription of cellular receptors formatrix proteins.

The anti-fibrotic activities of pirfenidone have been demonstrated invivo in laboratory animals with fibrotic lesions, in vitro with humanlung fibroblast (WI38) cell cultures, and observed through pilot opentrials in patients with severe pulmonary fibrosis, benign prostatehypertrophy, or keloids. Pirfenidone may selectively arrest scarenlargement, and remodels or removes scar tissue or fibrosis. Thedysfunction caused by fibrotic lesions may be ameliorated by thereduction or removal of the fibrotic lesion following pirfenidonetreatment. Apparently organ and tissue function can be restored, evenafter the presence of fibrosis for several years. When given immediatelyafter an insult, such as trauma, infection, or allergy, to a tissue,pirfenidone also may prevent formation of excessive scar tissue, orfibrotic lesions, and thus help retain normal function and appearance ofthe tissue.

Pirfenidone may cause removal of excessive collagenous fibrotic tissueby a phagocytic action of local fibroblasts. This has been observed byexamination of histological sections of lung tissue under the lightmicroscope from dogs, mice, rats, and hamsters with pulmonary fibrosistreated with pirfenidone, and also through the electron micrographs ofhistological sections of lung tissue taken from hamsters withexperimentally-induced asbestosis that were treated with pirfenidone. Noinfiltration of inflammation-inducing neutrophils, PMN cells, monocytes,lymphocytes occurred.

The enhanced proliferation of W138 fibroblasts upon in vitro exposure toPDGF or bFGF may be blocked by pirfenidone added to cell growth media.Pirfenidone may also inhibit the TGF-β1 induced rise in collagen outputin lung and dermal fibroblast cultures.

The human clinical findings after treatment with pirfenidone have beenconsistent with the anti-fibrotic effects observed in the laboratoryanimals. Pilot open clinical trials with oral pirfenidone have beenundertaken with patients afflicted with pulmonary asbestosis,bleomycin-induced pulmonary fibrosis, idiopathic pulmonary fibrosis,scleroderma with pulmonary fibrosis, and Hermansky-Pudlak Syndromecharacterized by pulmonary fibrosis.

The clinical criteria for beneficial response during the first months onpirfenidone included reduction in incidence of coughs, reduction insupplemental oxygen requirements, increased exercise tolerance, reduceddyspnea during exercise, amelioration of cor pulmonale, resumption ofnormal daily tasks, body weight gain, and survival. During the earlymonths, pulmonary function as gauged by chest x-ray, spirometry, or COdiffusion (DLCO) showed little, if any, change. However, after 4 to 6months on pirfenidone, inhibition or blocking of further deteriorationin lung function was evidenced by pulmonary function tests, vitalcapacity (VC), in the diffusing capacity of the lung for carbon monoxide(DLCO). These overall observations compare favorably with thosedescribed by Van Barneveld et al. (Amer. Rev. Respr. Dis., vol. 135,48-51, 1987), during the spontaneous recovery by patients frombleomycin-induced pulmonary pneumonitis (early stage fibrosis).

Martinet et al. (NE Jour. Med., vol 317, 202-209, 1987) have describedan exaggerated release of PDGF by alveolar macrophages in patients withidiopathic pulmonary fibrosis. The in vitro demonstration of inhibitionby pirfenidone of the mitogenesis and enhanced formation of collagencaused by growth factors (bFGF, PDGF, and TGF-β1) may partly explain thebeneficial in vivo anti-fibrotic action of pirfenidone.

In an open pilot trial of pirfenidone in older men with clinicallyadvanced benign prostate hypertrophy (BPH, non-cancerous fibrousenlargement of the male prostate gland), the patients experiencedfunctional improvement based on objective criteria. After taking oralpirfenidone the frequent urinary bladder urgency was ameliorated, andnocturia rarely recurred. In another pilot open trial, topicalapplications of pirfenidone ointment to surgical sites immediately afterkeloid resection has prevented recurrence of the keloids as observed intwo-year follow-ups in the patients. Each of those patients had a priorhistory of repeated early keloid re-growths after such surgery.Pirfenidone may induce a remodeling of skin fibrotic lesions to reduceor remove keloids, reduce or remove dermal scars, and remove or lessenthe contractures of hypertrophic (post burn injury) scars. In a similarcondition, pirfenidone also acts to inhibit post-operative surgicaladhesions.

Thus, clinical investigations under both controlled protocol designs andopen label trials have demonstrated that pirfenidone exertsanti-fibrotic and cytoprotective actions. The observed side effectsafter oral administration were relatively mild (drowsiness, gastricnausea or photosensitivity rash). No serious adverse reactions have beenreported.

In summary, based on the TNF-α inhibitor (cytoprotective) activity ofpirfenidone, the capsule formulation of the present disclosure may beadministered according to certain embodiments of this disclosure totreat patients suffering from the following disorders:

1) Central Nervous System syndromes: relapsing-remitting multiplesclerosis, primary and secondary multiple sclerosis, spinal multiplesclerosis, cerebral malaria, viral or bacterial infections of the CNS,bacterial meningitis, “autoimmune” disorders of the central nervoussystem (CNS), CNS stroke and infarction, brain edema, Parkinson'ssyndrome, Alzheimer's disease, amylotrophic lateral sclerosis (ALS), andbrain concussion or contusion;

2) Musculo-skeletal syndromes: rheumatoid arthritis, trauma-inducedarthritis, arthritis caused by a microbial infection, or by a parasite,tendonitis, and, arthritis induced by medical products or drugs(including small synthetic molecules as well as purified natural orsynthesized peptides or proteins);

3) Pulmonary syndromes: acute adult respiratory distress syndrome,asthma, allergic rhinitis, allergic conjunctivitis, chronic obstructivepulmonary disease (COPD), and lung sarcoidosis;

4) Systemic immunologic, inflammatory or toxic syndromes: endotoxemiashock syndrome, septic shock, graft-host disease, allograftvasculopathy, hemorrhagic shock, reperfusion injury of the brain ormyocardium, thermal burns, radiation injury, general or dermal traumaticor contusion injuries, eosinophilic granuloma, diabetic mellitus (typeII), or systemic lupus erythromatosus;

5) Gastro-intestinal syndromes: Crohn's disease, ulcerative colitis, andliver inflammatory disorders; and

6) Congestive heart failure.

Further, based on the anti-fibrotic activity of pirfenidone, the capsuleformulation of the present disclosure may be administered according toother embodiments to treat patients suffering from the followingdisorders: pulmonary fibrosis, radiation and drug-induced lung fibrosis,hepatic fibrosis, cardiac fibrosis, keloid, post-surgical adhesions,benign prostate hypertrophy in humans, arteriosclerosis, dermalfibrosis, and coronary restenosis.

It is to be understood that the description, specific examples and data,while indicating exemplary embodiments, are given by way of illustrationand are not intended to limit the various embodiments of the presentdisclosure. All references cited herein for any reason, are specificallyand entirely incorporated by reference. Various changes andmodifications within the present disclosure will become apparent to theskilled artisan from the description and data contained herein, and thusare considered part of the various embodiments of this disclosure.

1-36. (canceled)
 37. A method for preparing a granulation comprising5-methyl-1-phenyl-2-(1H)-pyridone and pharmaceutically acceptableexcipients, the method comprising the steps of preparing the granulationusing a type and an amount of an excipient selected to increase the AUCof the 5-methyl-1-phenyl-2-(1H)-pyridone upon oral administration, ascompared to 5-methyl-1-phenyl-2-(1H)-pyridone without excipients orallyadministered in a capsule shell.
 38. The method of claim 37 wherein themethod comprises the steps of preparing the granulation using a type andan amount of binder selected to increase the AUC of the5-methyl-1-phenyl-2-(1H)-pyridone upon oral administration, as comparedto 5-methyl-1-phenyl-2-(1H)-pyridone without excipients orallyadministered in a capsule shell.
 39. The method of claim 38, wherein thebinder is a binder that interacts with the amide carbonyl group of the5-methyl-1-phenyl-2-(1H)-pyridone.
 40. The method of claim 37, whereinthe pharmaceutically acceptable excipients comprise one or more of adisintegrator, a binder, a filler, and a lubricant.
 41. The method ofclaim 40, wherein said disintegrator comprises one or more of agar-agar,algins, calcium carbonate, carboxmethylcellulose, cellulose, clays,colloid silicon dioxide, croscarmellose sodium, crospovidone, gums,magnesium aluminium silicate, methylcellulose, polacrilin potassium,sodium alginate, low substituted hydroxypropylcellulose, andcross-linked polyvinylpyrrolidone hydroxypropylcellulose, sodium starchglycolate, and starch.
 42. The method of claim 40, wherein the bindercomprises one or more of microcrystalline cellulose, hydroxymethylcellulose, hydroxypropylcellulose, and polyvinylprryolidone.
 43. Themethod of claim 40, wherein said filler comprises one or more of calciumcarbonate, calcium phosphate, dibasic calcium phosphate, tribasiccalcium sulfate, calcium carboxymethylcellulose, cellulose, dextrates,dextrin, dextrose, fructose, lactitol, lactose, magnesium carbonate,magnesium oxide, maltitol, maltodextrins, maltose, sorbitol, starch,sucrose, sugar, and xylitol.
 44. The method of claim 40, wherein saidlubricant comprises one or more of agar, calcium stearate, ethyl oleate,ethyl laureate, glycerin, glyceryl palmitostearate, hydrogenatedvegetable oil, magnesium oxide, magnesium stearate, mannitol, poloxamer,glycols, sodium benzoate, sodium lauryl sulfate, sodium stearyl,sorbitol, stearic acid, talc, and zinc stearate.
 45. The method of claim40, wherein by weight of the granulation, said disintegrator is 2-10%,said binder is 2-30%, said filler is 2-30%, and said lubricant is0.3-0.8%.
 46. The method of claim 40, wherein the excipients comprisemagnesium stearate as a lubricant, microcrystalline cellulose as abinder, and croscarmellose sodium as a disintegrator.
 47. The method ofclaim 37, wherein, by weight of the granulation, the5-methyl-1-phenyl-2-(1H)-pyridone comprises 70-95% and thepharmaceutically acceptable excipients comprise 5-30%.
 48. The method ofclaim 37, wherein the granulation comprises 100-400 mg5-methyl-1-phenyl-2-(1H)-pyridone.
 49. The method of claim 37, whereinthe granulation comprises a wet-granulated mixture.